Serum- and bradykinin-induced calcium transients in familial Alzheimer's fibroblasts

McCoy, Kevin; Mullins, R. Dyche; Newcomb, Terry; Ng, Grace; Pavlínková, Gabriela; Polinsky, R. J.; Nee, Linda E.; Sisken, Jesse E.

doi:10.1016/0197-4580(93)90103-i

Cited by 36 publications

(19 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AD fibroblasts have an increased cytosolic calcium response to InsP 3 formation agonists (Peterson et al, , 1988Huang et al, 1991;McCoy et al, 1993;Etcheberrigaray et al, 1994;Ito et al, 1994). These reports are consistent with enhancement of InsP 3 -mediated calcium release in AD cybrids.…”

Section: Discussionsupporting

confidence: 79%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

237

138

View full text Add to dashboard Cite

Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to 0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4,5-triphosphate (InsP 3 )-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP 3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. ␤-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.

show abstract

Section: Discussionsupporting

confidence: 79%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

237

138

View full text Add to dashboard Cite

show abstract

“…Calcium imaging studies of cultured PC12 expressing PS-1 L286V have shown that this mutation alters calcium release from ER stores such that calcium responses to agonists that activate the IP 3 pathway (e.g., muscarinic cholinergic agonists and bradykinin) are enhanced greatly . The perturbed calcium homeostasis observed in PC12 cells expressing mutant PS-1 is consistent with reports that calcium signaling is altered in cultured fibroblasts taken from carriers of PS-1 mutations (McCoy et al, 1993;Ito et al, 1994). Our data suggest that disruption of calcium homeostasis by mutant PS-1 could be linked mechanistically to its proapoptotic action because dantrolene, an agent that blocks calcium release from ER, protected cells against the death-promoting effect of the PS-1 mutation.…”

Section: Discussionsupporting

confidence: 78%

Alzheimer’s Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid β-Peptide: Involvement of Calcium and Oxyradicals

et al. 1997

View full text Add to dashboard Cite

Most autosomal dominant inherited forms of early onset Alzheimer’s disease (AD) are caused by mutations in the presenilin-1 (PS-1) gene on chromosome 14. PS-1 is an integral membrane protein with six to nine membrane-spanning domains and is expressed in neurons throughout the brain wherein it is localized mainly in endoplasmic reticulum (ER). The mechanism or mechanisms whereby PS-1 mutations promote neuron degeneration in AD are unknown. Recent findings suggest links among deposition of amyloid β-peptide (Aβ), oxidative stress, disruption of ion homeostasis, and an apoptotic form of neuron death in AD. We now report that expression of the human PS-1 L286V mutation in PC12 cells increases their susceptibility to apoptosis induced by trophic factor withdrawal and Aβ. Increases in oxidative stress and intracellular calcium levels induced by the apoptotic stimuli were exacerbated greatly in cells expressing the PS-1 mutation, as compared with control cell lines and lines overexpressing wild-type PS-1. The antiapoptotic gene product Bcl-2 prevented apoptosis after NGF withdrawal from differentiated PC12 cells expressing mutant PS-1. Elevations of [Ca2+]iin response to thapsigargin, an inhibitor of the ER Ca2+-ATPase, were increased in cells expressing mutant PS-1, and this adverse effect was abolished in cells expressing Bcl-2. Antioxidants and blockers of calcium influx and release from ER protected cells against the adverse consequences of the PS-1 mutation. By perturbing cellular calcium regulation and promoting oxidative stress, PS-1 mutations may sensitize neurons to apoptotic death in AD.

show abstract

“…In this respect, Balin et al (1988) and Tesco et al (1993) reported that skin fibroblasts from Alzheimer's disease patients have the same growth properties as those from controls, suggesting that the fibroblast abnormalities found in Alzheimer's disease are related to the disease and not to in-vitro aging (Balin et al, 1988;Tesco et al, 1993). Previous reports of abnormalities in cultured fibroblasts from Alzheimer's disease patients include: altered Ca ++ metabolism (McCoy et al, 1993;Peterson et al, 1985Peterson et al, , 1986Peterson et al, , 1988, reduced acetylcholinesterase activity (Bartha et al, 1987), reduced secretion of a cholinergic neuron differentiation factor (Kessler, 1987), altered [3-adrenoceptor-stimulated cAMP formation (Huang and Gibson, 1993) and increased expression of the Alzheimer's disease [3-amyloid precursor protein (APP) gene in senescence (Adler et al, 1991).…”

Section: Introductionmentioning

confidence: 89%

Characterization of muscarinic acetylcholine receptors in cultured adult skin fibroblasts: Effects of the swedish Alzheimer's disease APP 670/671 mutation on binding levels

Vestling

Cowburn

Venizelos

et al. 1995

J Neural Transm Gen Sect

View full text Add to dashboard Cite

We have characterised the muscarinic receptor subtypes found in human skin fibroblasts and compared binding levels in cell lines from members of the Alzheimer's disease family with the Swedish amyloid precursor protein (APP) 670/671 mutation. Binding studies with [3H] quinuclidinyl benzilate ([3H]QNB) and the M2/M4 selective antagonist [3H] (+/-)-5,11-dihydro-11-([(2-[(di-propylamino)methyl]-1- piperidinyl]ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one ([3H]AF-DX 384) revealed the presence of a single population of muscarinic receptors on lysed fibroblast membranes. [3H]QNB binding was displaced by a number of selective muscarinic ligands with a rank order of potency: atropine > himbacine > methoctramine > (+/-)-p-fluoro-hexahydro-sila-difenidol hydrochloride > pirenzepine > muscarinic-toxin-3. APP 670/671 mutation carrying cell lines showed 25-35% lower levels of muscarinic receptors labelled with [3H]QNB, [3H]N-methyl scopolamine and [3H]AF-DX 384, compared to controls. This difference was not statistically significant due to large individual variation. It is concluded that muscarinic receptors on adult skin fibroblasts are predominantly of the M2 subtype. Since these cells do not possess M1 and M3 receptor subtypes, they are unlikely to provide a good model for studying muscarinic receptor regulation of APP processing.

show abstract

Serum- and bradykinin-induced calcium transients in familial Alzheimer's fibroblasts

Cited by 36 publications

References 37 publications

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Alzheimer’s Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid β-Peptide: Involvement of Calcium and Oxyradicals

Characterization of muscarinic acetylcholine receptors in cultured adult skin fibroblasts: Effects of the swedish Alzheimer's disease APP 670/671 mutation on binding levels

Contact Info

Product

Resources

About